Genistein Ameliorates the Ischemic State of Random Skin Flap by Regulating Macrophage Polarization Through AMPK / SIRT1 Signaling Pathway

ABSTRACT Random‐pattern skin flaps are essential in reconstructive surgery but are frequently compromised by ischemic necrosis. Genistein (GST), a soy‐derived isoflavone, possesses antioxidant and anti‐inflammatory properties and has demonstrated protective effects in various ischemic disorders. However, its role and mechanism in improving flap survival remain unclear. A murine random‐pattern skin flap model and bone marrow‐derived macrophages (BMDMs) were used. In vivo, flaps were treated with different doses of genistein to determine the optimal concentration and to assess its effects on survival, angiogenesis, oxidative stress, and apoptosis. In vitro, BMDMs were stimulated with LPS and treated with genistein, with or without AMPK (Compound C) or SIRT1 (EX‐527) inhibitors, to investigate macrophage polarization and the underlying AMPK/SIRT1 signaling pathway. Genistein administration significantly improved flap survival area, enhanced blood perfusion, promoted angiogenesis, and reduced oxidative stress and apoptosis. Mechanistically, genistein induced a phenotypic shift in macrophages from the pro‐inflammatory M1 to the anti‐inflammatory M2 type. This effect was mediated by the activation of the AMPK/SIRT1 signaling pathway. Critically, the beneficial effects of genistein on both macrophage polarization and flap survival were abolished upon pharmacological inhibition of AMPK or SIRT1. Genistein enhances the survival of random‐pattern skin flaps by reprogramming macrophage polarization from M1 to M2 via the AMPK/SIRT1 signaling pathway. This study reveals a novel molecular mechanism for genistein's protective effect and highlights its potential as a therapeutic strategy to improve outcomes in reconstructive surgery.